Kidneys are excretory organs that serve the general function of maintaining the chemical and physical constancy of blood and other body fluids. They remove superfluous water and biologically useless as well as toxic materials that accumulate in the blood.
In vertebrates, the kidneys are paired, bean-shaped organs, with each kidney having a convex lateral or external border, and a medial, internal border which is concave in the center and convex toward either extremity. The central part of the medial border has a deep fissure called the hilum, through which extends vessels, nerves and the ureter. The hilum expands into a central cavity called the renal sinus. Each kidney is surrounded by a smooth, fibrous capsule and is comprised of an internal medullary surrounded by an external cortical substance. The medullary substance consists of striated conical masses termed renal pyramids, arranged such that their bases are directed toward the lateral border, while their apices converge toward the renal sinus. The cortical substance lies immediately beneath the fibrous capsule and arches over bases of the pyramids and extends between adjacent pyramids towards the renal sinus.
Microscopically, the kidney is comprised of a number of functional units called nephrons. The human kidney is comprised of about 1.25 million nephrons. Each nephron has a complex structure with two main parts: the glomerulus and the renal tubule. The glomerulus is a tuft of nonanastomosing capillaries located in the cortical substance which is derived from an arteriole called the afferent vessel which branches to form the capillary loops. The capillaries join to form the efferent arteriole The glomerulus is surrounded by a double-walled membranous sac called the capsule of Bowman, which is part of the renal tube. The renal tubule is located partly in the cortical substance, where it pursues a convoluted, circuitous course and forms the capsule of Bowman, and partly in the medullary substance, in which the convolutions of the tubule disappear. As it enters the medullary substance, it becomes straight, and dips down for a variable depth, then bends to form the loop of Henle and ascends back into the cortical substance where it again becomes tortuous and terminates into a collecting tubule which opens into a ureter. The ureter opens into the urinary bladder.
During embryogenesis, the rudiments of the permanent kidneys, the metanephros, make their appearance during the fifth week of gestation in humans, during day 12 of embryonic rat development and during day 11 of embryonic mouse development. At this stage of development, outgrowths of the mesonephric ducts, called ureteric buds, collect about their distal ends, intermediate mesoderm caudal to the mesonephros, designated metanephric blastema. Numerous outgrowths arise from the distal end of the ureteric bud which push radially into the surrounding mass of metanephric blastema and give rise to the collecting ducts of the kidneys. The proximal ends of the ureteric bud give rise to the ureter and renal pelvis. The metanephric blastema differentiates into all of the tubular structures of the adult renal tubule with the exception of the collecting system. Nephron segment growth and differentiation that occurs in metanephric organ culture recapitulates closely that which occurs in vivo. One exception is that vascularization of the nephron does not take place in the metanephric organ culture system because the origin of the glomerular blood vessels is, in part, extrametanephric. Humans develop a full complement of nephrons by approximately 35 weeks of gestation. However, in rodents nephrogenesis is not complete at the time of birth, but rather continues for the first 3 weeks following birth, when nephrons continue to develop from a nephrogenic zone located at the periphery of the kidney.
Once renal development is complete, no new nephrons are formed under any conditions. Renal arteries deliver blood to the glomerulus, where blood plasma is filtered through the porous walls of the capillaries. The filtrate drains into the tube system where the major part of water and plasma components are reabsorbed into the blood vessels. The remaining liquid containing biologically useless materials in a high concentration is the urine that passes through the ureter to the urinary bladder. Urine contains hundreds of organic compounds, including the protein digestion and metabolism products, urea, creatinine, uric acid and others. The loss of functional renal mass that occurs following insults to the adult kidney, is compensated for in the short term, by hypertrophy and hyperfunction of the remaining nephrons. However, these compensatory changes are often transient and under some circumstances maladaptive in that they may lead to further loss of functional renal mass. When kidneys cannot operate properly, useless and/or toxic materials accumulate in blood and other physiological fluids and can lead to illness and death.
End-stage chronic renal failure in humans afflicts more than 250,000 individuals in the United States, most of whom are treated using dialysis. External hemodialysis removes excess water and biologically useless organic compounds from the patient. A drawback of this treatment results from the unselectivity of the diffusion process through the polymeric membrane that is used, which does not distinguish between useless molecules and useful molecules, such as amino acids, nucleotides, mineral ions and many other useful components. Additionally, the treatment is generally unpleasant for the patient because before dialysis, the waste products build up in the body, and after dialysis there is an imbalance of chemical equilibria and processes in the body due to removal of essential components. Thus, considerable morbidity is associated with dialysis treatment. Additionally, hemodialysis is an expensive, time-consuming process, which keeps the patient connected to the dialysis machine for several hours, three or four times a week.
Another method of treating kidney failure is to replace the malfunctioning kidneys with a functioning kidney from a donor organism. In the United States approximately 5,000 kidneys transplantations are performed annually. Because the kidneys are paired organs, and only one is necessary for normal life, live volunteer donors, in addition to cadaveric donors, can be used to provide the donor kidney. The drawbacks associated with transplantation are the availability of donor kidneys and immunological rejection by the transplant recipient of the donor organ.
Attempts have been made to increase renal mass by allogeneic kidney grafting. Woolf et al. transplanted pieces of metanephric tissue from embryonic mice into tunnels made into the renal cortex of recipient neonatal mice (less than one day old) which were still undergoing nephrogenesis [Kidney International, Vol. 38 (1990), .paragraph.. 991-997; and American J. of Kidney Diseases, Vol. XVII, No. 6 (June 1991) .paragraph.. 611-614]. Two to four weeks later, the chimeric kidneys were removed from the mice. The donor tissue was observed to contain mature, functioning, differentiated features within the nephrons which indicated that post-transplantation differentiation occurred within the donor metanephric tissue. When adult mice were grafted with pieces of metanephric tissue, using the same procedure that was used for the neonatal mice, the donor tissue was extruded from the cortex and resembled a poorly-differentiated tumor underneath the renal capsule. The investigators concluded that the neonatal kidney, which in mice still undergoes nephrogenesis after birth, can facilitate differentiation of an embryonic implant, but that this ability is lacking in the fully-differentiated adult kidney.
Barakat and Harrison, J. Anat. (1971), Vol.110, 3, .paragraph.. 393-407, sectioned metanephroi originating from embryonic rats (days 15-17) and kidneys from newborn rats (&lt;1 day), into quarters, and transplanted each quarter into a subcutaneous site in the abdominal wall of either a newborn or adult rat. Within the newborn hosts, the grafts formed fully differentiated glomeruli and tubules by 8 days post-transplantation. However, with the adult hosts, there was significant lymphocytic infiltration into the grafts after the same amount of time. By 11 to 12 days, the grafts within the adult hosts were largely replaced by fibrosis. Irrespective of whether the grafted renal tissue was of fetal or neonatal origin, each of the adult host rats rejected its graft.
Abrahamson et al. transplanted whole embryonic (day 17) rat kidneys under the renal capsule of mature rat hosts [Laboratory Investigation, Vol. 64, No. 5, .paragraph.. 629-639 (1991)]. Considerable glomerulogenesis and tubulogenesis occurred, although structural abnormalities were present. While, the implanted kidneys had become connected to the host vasculature, no observations were made as to whether functioning nephrons were present.
Signs of rejection were apparent in all of the grafts within 10 days post-transplantation.
Immunosuppression treatments have been used to prevent rejection of allografts. Churchill et al. performed experiments where the left kidneys of adult rats were removed and replaced by donor adult rat kidneys [Transplantation, Vol. 49: 8-13 (1990)]. Non-immunosuppressed recipients rejected the transplanted kidneys, while rejection was prevented in recipients immunosuppressed with daily injections of Cyclosporine A.